Introduction
Background
Thalassemic syndromes are genetically determined disorders of hemoglobin synthesis with decreased production of either alpha or beta polypeptide chains of hemoglobin molecules, which results from markedly decreased amounts of globin messenger ribonucleic acid. The imbalance may result from many genetic lesions.
Pathophysiology
Normal adult hemoglobin is a large complex molecule in which an iron-containing pigment (heme) is conjugated to a complex protein (globin). The globin component consists of a tetrad of 574 amino acids in the form of 2 pairs of unlike polypeptide chains designated by Greek letters. Each molecule consists of 2 alpha and 2 nonalpha chains (eg, beta, gamma, delta) that have well-recognized and consistent amino acid sequences. In the normal adult hemoglobin (HbA), which constitutes over 95% of the hemoglobin in normal persons older than 1 year, the globin component consists of 2 alpha and 2 beta chains (alpha2beta2); the remaining hemoglobin comprises HbA2 (alpha2delta2) and fetal hemoglobin (HbF or alpha2gamma2).
Thalassemia. Lateral skull radiograph. Widening of the calvarium is present; the outer table overlying the frontal region is obliterated and new bone formation can be seen in the diploë, producing a "hair-on-end" appearance. Note that the occipital bone is uninvolved. The impressions of the calvarial vessels are enlarged.
Thalassemia. Radiograph of the ribs. Erosions of the inferior cortical margins of the third, fourth, and fifth ribs are noted.
The most important thalassemic syndrome is homozygous beta thalassemia, in which the production of beta chains is markedly decreased or absent, and a consequent decrease in synthesis of total hemoglobin occurs. This results in severe hypochromic anemia. Furthermore, excess alpha chains, which synthesize at the normal rate, precipitate as insoluble inclusion bodies within the erythrocytes and their precursors. The presence of such intracellular inclusion bodies leads to increased erythrocyte hemolysis and to severe ineffective hematopoiesis. Approximately 70-85% of marrow normoblasts are destroyed in severely affected patients. These processes result in profound anemia and an associated increase in marrow activity, which is estimated to increase 5- to 30-fold.
Frequency
United States
An estimated 800-1000 patients have homozygous beta thalassemia in the United States. Most of these patients live in the Northeast between Boston and New York. The heterozygous trait occurs in 2.5% of Italian Americans and 7-10% of Greek Americans.
International
In high-risk areas (ie, Greek and Italian islands), 10% of the population may have homozygous beta thalassemia.
Mortality/Morbidity
Thalassemia major, the homozygous state, is a serious condition that usually becomes apparent within the first year of life. In the untreated patient, hemolysis and profound anemia lead to marrow hypertrophy and hyperplasia. The anemia may be so severe that death may occur in the first 5 years, although regular blood transfusions can prolong life. The long-standing erythrocyte breakdown results in chronic overproduction of bilirubin, which predisposes the patient to formation of pigmentary gallstones and to hemosiderosis resulting from the deposition of excess iron in the reticuloendothelial system, particularly the myocardium, liver, and pancreas. Death from the effects of hemosiderosis may occur before age 25 years. However, since there is a spectrum of severity, some patients may be only mildly affected.
Race
The disorder is common, but not exclusively found, in races bordering the eastern Mediterranean Sea or in families originating from these areas (thalassa means "sea" in Greek). Thalassemia has been identified in people who are Greek, Italian, Slavic, Algerian, Moroccan, Egyptian, Syrian, Armenian, Bukharan, Jewish, Persian, German, Indian, Burmese, Thai, Singhalese, Chinese, Filipino, Mexican, and British. The highest concentrations of the disease are found in Greece, including the Greek islands; in parts of Italy, in particular, the lower Po valley; in southern Italy; and in the Italian islands. Sicily, Corsica, and Sardinia (Italian islands) and Cyprus and Crete (Greek islands) are heavily affected in particular; the higher incidence in these islands likely is because of the higher inbreeding that occurs in isolated populations.
Sex
Male-to-female ratio is equal.
Age
Thalassemia is a genetic disorder that usually does not become apparent until patients are older than 6 months. Survival after age 30 years once was uncommon, but the prognosis has improved through the use of a regimen of hypertransfusion in conjunction with chelation therapy.
Anatomy
Changes that occur in the osseous system of patients with thalassemia major are the result of marrow hypertrophy and hyperplasia in response to chronic anemia. Since hematopoietic marrow normally is found in the axial skeleton and in the proximal portions of the appendicular skeleton, osseous changes are most commonly found in these sites. In infants and children, hematopoietic marrow is distributed throughout the axial and appendicular skeleton, and, consequently, osseous changes may be present distally as far as the phalanges. Abnormalities in the appendicular skeleton become less pronounced as normal developmental regression of red marrow occurs; however, in the presence of severe, prolonged anemia, regression does not occur, and appendicular findings may persist.
Presentation
The diagnosis is established in infancy by the onset of a severe hypochromic anemia with splenomegaly and markedly elevated levels of HbF. Family studies show both parents as carriers of the beta-thalassemic trait, which is marked by mild, microcytic, hypochromic anemia and high levels of HbA2.
Early signs and symptoms are associated with the anemia, which is characterized by hypochromic, microcytic red cells with variable numbers of nucleated erythrocytes and reticulocytes. Many of the erythrocytes and their precursors reveal evidence of inclusion bodies (Fessas bodies) consisting of denatured alpha-globin. Pallor, icterus, and cardiac enlargement occur frequently. Marrow hypertrophy and extramedullary hematopoiesis may result in hepatosplenomegaly, as well as skull and facial deformities, in particular, prominence of malar eminences and malalignment of teeth, which gives rise to the characteristic "rodent facies."
Pathologic fractures may occur but are less common than suggested from the radiographic appearance of the bones, which may be explained by the sedentary lifestyle forced upon these patients by their disease process. In the untreated and undertransfused patient, growth retardation is noticeable in the second decade; adults usually are short, and the appearance of secondary sexual characteristics is retarded. Terminal events, including congestive heart failure and arrhythmia, hepatic failure or cirrhosis, and diabetes mellitus, are associated with siderosis of the myocardium, liver, or pancreas.
Before 1965, because of concerns about transfusion-induced iron overload, patients with homozygous beta thalassemia were transfused infrequently to maintain a hemoglobin level just compatible with reasonable activity. The hemoglobin level often was allowed to fall as low as 5-6 g/100 mL. Since that time, patients have been treated with a more aggressive transfusion regimen consisting of transfusions of 15 mL/kg of packed red blood cells every 3-5 weeks to maintain the hemoglobin level above 9.5-10 g/100 mL.
Since 1977, long-term chelation therapy has been used to eliminate excess iron. This treatment, which consists of a slow (ie, overnight) subcutaneous injection of 1.5-2 g deferoxamine 5-6 times per week, creates a negative iron balance, which means that deferoxamine-induced iron excretion exceeds iron delivery by transfusion. Administration of high subcutaneous doses of deferoxamine to young children (before iron overload is established) is associated with a significant decrease in mean body length, joint stiffness, and a ricketslike syndrome.
Patients with thalassemia intermedia are an interesting subset of those with thalassemia, constituting 5-10% of patients with thalassemia major. These patients are able to maintain levels of hemoglobin compatible with an active life (6-9 g/dL) without regular transfusions. They have a milder clinical form of the disease and a longer life expectancy; however, in many patients, this appears to be at the expense of extensive marrow hypertrophy and associated skeletal deformities.
Preferred Examination
Plain radiographs usually are all that are required to confirm the diagnosis. The complete skeleton is involved. The most fruitful areas to radiograph are as follows:
- Anteroposterior (AP) of both hands
- Lateral skull
- AP and lateral of thoracolumbar spine
- AP of abdomen for gallstones
- AP of chest for cardiomegaly, congestive heart failure, and extramedullary hematopoiesis
Limitations of Techniques
Conventional radiography usually confirms the diagnosis.
CT may be required to further evaluate faciomaxillary changes and to clearly define expansile lesions of the pelvis resulting from extramedullary hematopoiesis.
Conventional radiography may not show early extramedullary hematopoiesis, which is best seen on MRI.
Differential Diagnoses
Other Problems to Be Considered
Other chronic anemias
Acute leukemia
More on Thalassemia |
 Overview: Thalassemia |
| Imaging: Thalassemia |
| Multimedia: Thalassemia |
| References |
| Further Reading |
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References
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Hankins JS, McCarville MB, Loeffler RB, Smeltzer MP, Onciu M, Hoffer FA, et al. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood. Mar 4 2009;[Medline].
Christoforidis A, Perifanis V, Spanos G, Vlachaki E, Economou M, Tsatra I, et al. MRI assessment of liver iron content in thalassamic patients with three different protocols: comparisons and correlations. Eur J Haematol. Feb 10 2009;[Medline].
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Caffey J. Cooley's anemia: a review of the roentgenographic findings in the skeleton. AJR Am J Roentgenol. 1957;78:381.
Cooley TB, Witwer ER, Lee P. Anemia in children with splenomegaly and peculiar changes in the bones. Am J Dis Child. 1927;34:347.
Currarino G, Erlandson ME. Premature fusion of the epiphyses in Cooley's anemia. Radiology. 1964;83:656.
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Lawson JP, Ablow RC, Pearson HA. Calvarial and phalangeal vascular impressions in thalassemia. AJR Am J Roentgenol. Sep 1984;143(3):641-5. [Medline].
Lawson JP, Ablow RC, Pearson HA. Premature fusion of the proximal humeral epiphyses in thalassemia. AJR Am J Roentgenol. Feb 1983;140(2):239-44. [Medline].
Lawson JP, Ablow RC, Pearson HA. The ribs in thalassemia. I. The relationship to therapy. Radiology. Sep 1981;140(3):663-72. [Medline].
Lawson JP, Ablow RC, Pearson HA. The ribs in thalassemia. II. The pathogenesis of the changes. Radiology. Sep 1981;140(3):673-9. [Medline].
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Further Reading
Related eMedicine topics
Thalassemia, Alpha
Thalassemia, Beta
Thalassemia Intermedia
Thalassemia (from Pediatrics: General Medicine)
Hemosiderosis
Clinical guidelines
Hemoglobinopathies in Pregnancy
Clinical studies
Evaluating People With Thalassemia: The Thalassemia Longitudinal Cohort (TLC) Study
Evaluating the Safety of G-CSF Mobilization in Individuals With Beta Thalassemia Major
Keywords
thalassemia, Cooley anemia, Mediterranean anemia, erythroblastic anemia
